Catechol-O-methyltransferase (COMT; EC2.1.1.6) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure.[6] In humans, catechol-O-methyltransferase protein is encoded by the COMTgene.[7] Two isoforms of COMT are produced: the soluble short form (S-COMT) and the membrane bound long form (MB-COMT). As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines.[8] COMT was first discovered by the biochemistJulius Axelrod in 1957.[9]

Levodopa, a precursor of catecholamines, is an important substrate of COMT. COMT inhibitors, like entacapone, save levodopa from COMT and prolong the action of levodopa.[10] Entacapone is a widely used adjunct drug of levodopa therapy. When given with an inhibitor of dopa decarboxylase (carbidopa or benserazide), levodopa is optimally saved. This "triple therapy" is becoming a standard in the treatment of Parkinson's disease.

Soluble COMT can also be found extracellularly, although extracellular COMT plays a less significant role in the CNS than it does peripherally.[19]:210 Despite its importance in neurons, COMT is actually primarily expressed in the liver.[19]:135

A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase results in a valine to methionine mutation at position 158 (Val158Met) rs4680.[14] The homozygous Val variant metabolizes dopamine at up to four times the rate of its methionine counterpart.[21] However, the Met variant is overexpressed in the brain,[23][unreliable medical source] resulting in a 40% decrease in functional enzyme activity.[24][unreliable medical source] The lower rates of catabolisis for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the post-synaptic neuron. Given the preferential role of COMT in prefrontal dopamine degradation, the Val158Met polymorphism is thought to exert its effects on cognition by modulating dopamine signaling in the frontal lobes.

Comparable effects on similar cognitive tasks, the frontal lobes, and the neurotransmitter dopamine have also all been linked to schizophrenia. It has been proposed that an inherited variant of COMT is one of the genetic factors that may predispose someone to developing schizophrenia later in life, naturally or due to adolescent-onset cannabis use.[28][unreliable medical source] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on schizophrenia development.[29][unreliable medical source]

It is increasingly recognised that allelic variation at the COMT gene are also relevant for emotional processing, as they seem to influence the interaction between prefrontal and limbic regions. Research conducted at the Section of Neurobiology of Psychosis, Institute of Psychiatry, King's College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives,[30][unreliable medical source] but these findings have not been replicated so far.

The COMT Val158Met polymorphism also has a pleiotropic effect on emotional processing.[30][unreliable medical source][31][unreliable medical source] Furthermore, the polymorphism has been shown to affect ratings of subjective well-being. When 621 women were measured with experience sample monitoring, which is similar to mood assessment as response to beeping watch, the met/met form confers double the subjective mental sensation of well-being from a wide variety of daily events. The ability to experience reward increased with the number of ‘Met’ alleles.[32][unreliable medical source] Also, the effect of different genotype was greater for events that were felt as more pleasant. The effect size of genotypic moderation was quite large: Subjects with the val/val genotype generated almost similar amounts of subjective well-being from a ‘very pleasant event’ as met/met subjects did from a ‘bit pleasant event’. Genetic variation with functional impact on cortical dopamine tone has a strong influence on reward experience in the flow of daily life.[32] In one study participants with the met/met phenotype described an increase of positive affect twice as high in amplitude as participants with the val/val phenotype following very pleasant or pleasant events.[32][unreliable medical source]

One review found that those with Val/Val tended to be more extroverted, more novelty seeking and less neurotic than those with the Met/Met allele[33]

Temporomandibular joint dysfunction (TMD) does not appear to be a classic genetic disorder, however variations in the gene that codes for COMT have been suggested to be responsible for inheritance of a predisposition to develop TMD during life.[34]

^Jatana N, Apoorva N, Malik S, Sharma A, Latha N (January 2013). "Inhibitors of catechol-O-methyltransferase in the treatment of neurological disorders"(PDF). Central Nervous System Agents in Medicinal Chemistry. 13 (3): 166–94. doi:10.2174/1871524913666140109113341. PMID24450388. Two of the nitrocatechols, entacapone ... and tolcapone ... have been demonstrated to reduce the dose of L-DOPA required and also cause improvement in clinical symptoms, although tolcapone emerged to be more efficacious due to its greater bioavailability and a longer half-life when compared to entacapone. However, tolcapone is clinically restricted owning to its increased hepatotoxicity and other related digestive disorders.